Cardiovascular disease is a major health risk throughout the industrialized world. An estimated 80.7 million Americans suffer from one or more types of cardiovascular disease, including high blood pressure, coronary heart disease, heart failure, and stroke (Heart Disease and Stroke Statistics, American Heart Association, 2008). Cardiovascular disease was the cause of 57 percent of the deaths in 2004, and every year since 1900 (except 1918), cardiovascular disease accounts for more deaths than any other single cause or group of causes in the United States.
One of the most well-known types of cardiovascular disease is myocardial infarction (MI), commonly known as a heart attack. Estimates for 2005 show that 8.1 million people in the United States suffer from MI (Heart Disease and Stroke Statistics, American Heart Association, 2008). MI is caused by a sudden and sustained lack of blood flow to an area of the heart, typically caused by narrowing of a coronary artery. Without adequate blood supply, the tissue becomes ischemic, leading to the death of myocytes and vascular structures. This area of necrotic tissue is referred to as the infarct site, and will eventually become scar tissue. Survival is dependent on the size of this infarct site, with the probability of recovery decreasing with increasing infarct size. For example, in humans, an infarct of 46% or more of the left ventricle triggers irreversible cardiogenic shock and death.
Myocardial regeneration involves the replacement of cells lost following injury, such as an ischemic injury. Damage creates a barrier to restitutio ad integrum and promotes the initiation of a healing process that leads to scar formation (Leri et al. 2005). However, the scar does not possess the biochemical, physical and functional properties of the original tissue. Effective cardiac repair necessitates creating myocardium de novo that closely resembles the morphology of the normal adult heart.
Successful regeneration of myocardial tissue after acute infarction has been achieved by employing cardiac stem cells (CSCs). Administration of autologous CSCs to the damaged myocardium or local activation of resident CSCs by intramyocardial administration of growth factors results in a significant recovery of ventricular muscle mass. However, the regenerated myocytes are small and have the characteristics of fetal-neonatal cells (Beltrami et al., 2003; Urbanek et al., 2005; Linke et al., 2005; and Bearzi et al. 2007). Thus, one of the major problems in cardiac repair is the lack of maturation of the newly formed cardiomyocytes. This problem is even more apparent when bone marrow progenitor cells (BMPCs) are employed for myocardial repair. Mobilization of BMPCs with cytokines or direct implantation of BMPCs in proximity of an infarct typically shows BMPC transdifferentiation with the generation of a large number of immature cardiomyocytes. Unfortunately, these cells rarely increase in size over time and fail to attain the properties of fully developed adult myocytes.
Thus, it is desirable to develop methods of facilitating the differentiation of CSCs and BMPCs into fully mature cardiomyocytes. Such methods would significantly improve stem cell-mediated treatment of myocardial infarctions and provide new approaches to the management of human heart failure.